Enteroendocrine cells, which are endocrine cells present in the epithelium in the gastrointestinal tract, secrete gut hormones or neuropeptides in response to stimuli by the substances introduced into the intestinal lumen. The same substances secreted by them are called hormones if they act on target organs by being transported there via the bloodstream or neuropeptides if they act as signaling molecules for activation of vagus nerves.
The gut hormones or neuropeptides secreted by the enteroendocrine cells include glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), serotonin (5-hydroxytryptamine, 5-HT), etc.
First, GLP-1 is secreted by L cells which are enteroendocrine cells present in the ileum and the colon.
GLP-1 is known to be effective in treating diabetes mellitus, treating obesity, treating heart diseases, regulating secretion and absorption of digestive enzymes [Mourad F H & Saade N E, Neural regulation of intestinal nutrient absorption. Progress in Neurobiology (2011) 95, 149-162], enhancing immunity [Campbell J E and Drucker D J, Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metabolism (2013) 17, 819], treating arteriosclerosis [Burgmaier M et al., Glucagon-like peptide-1 (GLP-1) and its split products GLP-1(9-37) and GLP-1(28-37) stabilize atherosclerotic lesions in apoe mice. Atherosclerosis (2013) 231, 427-435], treating cerebrovascular diseases and neuroinflammation (Salcedo I et al., Neuroprotective and neurotrophic actions of glucagon-like peptide-1 (GLP-1): an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. British Journal of Pharmacology (2012) 166, 1586-1599), and so forth.
It is involved in the treatment of diabetes through glucose-dependent stimulation of insulin secretion, increase of Insulin gene expression, promotion of proliferation of pancreatic beta cells, enhancement of survival of pancreatic beta cells, suppression of glucagon secretion, decrease of blood sugar level, etc. in the pancreas. Also, it is involved in the treatment of obesity by slowing the gastric emptying rate, suppressing appetite, increasing satiety and suppressing food intake.
In addition, it is known to be effective in treating heart diseases by protecting cardiomyocytes from ischemia and improving heart functions of patients and be involved in the regulation of digestion and absorption through secretion of digestive enzymes in the pancreas and the small intestine (Sokos, G. G. et al., Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J. Card. Fail. (2006) 12. 694-699., Ban, K., et al., Cardioprotective and vasodilatory actions of glucagon-like peptide-1 receptor are mediated through both glucagon-like peptide-1 receptor-dependent and -independent pathways. Circulation (2008) 117: 2340-2350).
It is known that the secretion of GLP-1 is promoted by the activation of TGR5 (C protein-coupled bile acid receptor 131, GPR131) and GPR119 (G-protein coupled receptor 119) which are G protein-coupled receptors (GPCRs) (Reimann, F., et al., Glucose sensing in L cells: a primary cell study. Cell Metab. (2008) 8: 532-539; Lauffer, L. M., et al., GPR119 is essential for oleoylethanolamide-induced glucagon-like peptide-1 secretion from the intestinal enteroendocrine L cell. Diabetes (2009) 58:1058-1066) or by the activation of α-gustducin (Jang, H. J., et al., 2007. Gut expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proceeding of the National Academy of Science 104, 15069-15074.). In particular, it is known that the activation of the G protein-coupled receptor (GPCR) TGR5 (G protein-coupled bile acid receptor 131, GPR131) expressed in brown adipose tissue and muscle is effective in treating obesity by increasing energy consumption and is related with the improvement of liver diseases (Lieu T et al., GPBA: A G protein-coupled receptor for bile acids and an emerging therapeutic target for disorders of digestion and sensation. British Journal of Pharmacology (2014) in press) and suppresses arteriosclerosis (Pols T W H et al., TGR5 activation inhibits atherosclerosis by reducing macrophage inflammation and lipid loading. Cell Metabolism (2011) 14, 747).
Next, CCK is synthesized and secreted by I-cells which are enteroendocrine cells present in the duodenum and the jejunum. Being secreted in the duodenal mucosa, CCK is known to induce anti-diabetic effect by suppressing glucose production through activation of the CCK-A receptor on the vagus nerves, provide anti-obesity effect by suppressing food intake and be involved in the regulation of digestion and absorption.
It is known that G protein-coupled receptors (GPCRs) and signaling molecules (G proteins, PLCβ2 (phospholipase Cβ2)), transient receptor potential (TRP) channels, etc. are involved in the secretion of CCK (FEBS Letters (2008) 582: 229-232).
And, 5-HT, which is a hormone secreted by enterochromaffin (EC) cells present in the whole gastrointestinal tract, is known to be involved in the regulation of digestion and absorption and provide anti-obesity effect by suppressing appetite (Gershon, M. D., Tack, J. (2007) The serotonin signaling system: from basic understanding to drug development for functional GI disorders. Gastroenterology 132, 397-414).
It is known that the secretion of gut hormones or neuropeptides plays a role in maintaining homeostasis related with food intake and digestive action (intestinal motility, secretion of digestive enzymes, appetite control, etc.). The homeostasis refers to the balance between the energies absorbed and consumed. If the balance is broken, it may cause diabetes, cardiovascular diseases, etc.
Globally, there have been consistent efforts to develop drugs effective for diabetes, cardiovascular diseases and other severe diseases. However, it is not easy to develop a drug which is very effective but has few side effects such as obesity, hepatotoxicity and edema.
Meanwhile, although drugs having anti-obesity effect are used for prevention or treatment of obesity, these drugs are known to induce side effects such as oily stools, abdominal inflation, dizziness, dry mouth, constipation, increased blood pressure, etc. Accordingly, development of natural functional substances which are safer and have stronger efficacy is required.